Version October 2024
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and for emergence of suicidal thoughts and behaviors. Mirtazapine is not approved for use in pediatric patients.
Dosage guidance:
Dosing: Some experts suggest a lower starting dose of 7.5 mg daily, particularly in patients with anxiety who are sensitive to antidepressant-associated overstimulation effects (eg, anxiety, insomnia) (Ref).
Headache, chronic tension-type, prophylaxis (alternative agent) (off-label use): Oral: Initial: 15 mg once daily at bedtime; may increase after 1 week to 30 mg/day based on response and tolerability (Ref).
Panic disorder (alternative agent) (off-label use):
Note: For patients nonresponsive to selective serotonin reuptake inhibitors (SSRIs) (Ref).
Oral: Initial: 15 mg once daily at bedtime; may increase in increments of 15 mg at intervals of no less than 1 week based on response and tolerability, up to a usual maximum of 45 mg once daily (Ref). Average doses in clinical trials were ~30 mg/day; doses up to 60 mg/day have been evaluated (Ref).
Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for ≥4 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (Ref). For brief treatment (eg, 2 to 3 weeks), may taper over 1 to 2 weeks; <2 weeks of treatment generally does not warrant tapering (Ref). Reasons for a slower taper (eg, over 4 weeks) include prior history of antidepressant withdrawal symptoms or high doses of antidepressants (Ref). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Ref). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (Ref). Evidence supporting ideal taper rates is limited (Ref).
Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from an MAOI. A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between two SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, and pharmacodynamics), and the degree of symptom control desired (Ref).
Switching to or from an MAOI:
Allow 14 days to elapse between discontinuing an MAOI and initiation of mirtazapine.
Allow 14 days to elapse between discontinuing mirtazapine and initiation of an MAOI.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function:
There are no dosage adjustments provided in the manufacturer's labeling; however, clearance is decreased in kidney impairment (Ref). Use with caution.
eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary (Ref).
eGFR <30 mL/minute/1.73 m2: Initial: 7.5 to 15 mg once daily; titrate slowly with close monitoring for adverse effects (Ref).
Hemodialysis, intermittent (thrice weekly): Unlikely to be significantly dialyzed due to high protein binding and large Vd (Ref):
Initial: 7.5 to 15 mg once daily; titrate slowly with close monitoring for adverse effects (Ref).
Peritoneal dialysis : Unlikely to be significantly dialyzed due to high protein binding and large Vd (Ref):
Initiate at 7.5 to 15 mg once daily and titrate slowly with close monitoring for adverse effects (Ref).
CRRT: Initial: 7.5 to 15 mg once daily; titrate slowly with close monitoring for adverse effects (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Initial: 7.5 to 15 mg once daily; titrate slowly with close monitoring for adverse effects (Ref).
There are no dosage adjustments provided in the manufacturer’s labeling; however, dosage reductions may be necessary in patients with moderate to severe hepatic impairment (clearance may be decreased). Some experts recommend reducing initial dose by 50% and a maximum dose of 30 mg/day in patients with hepatic impairment (Ref). Use with caution.
Major depressive disorder (unipolar): Oral: Initial starting doses of 7.5 mg once daily at bedtime have been suggested (Ref). Use with caution; clearance may be reduced; refer to adult dosing.
Discontinuation of therapy: Refer to adult dosing.
Switching antidepressants: Refer to adult dosing.
Antidepressants (when used without a mood stabilizer) may precipitate a mixed/manic episode in patients with bipolar disorder. Treatment-emergent mania or hypomania in patients with unipolar major depressive disorder (MDD) treated with mirtazapine have been reported rarely. Although some of these cases occurred in patients receiving monotherapy at a therapeutic antidepressant dose, a number of the reports occurred in patients also receiving selective serotonin reuptake inhibitors (SSRIs) (or without a period of washout from a previous SSRI) or had potential risk factors for switching (Ref). It has also been suggested that mirtazapine-induced mania may present with atypical features, consisting of dysphoria, irritability, insomnia, psychomotor agitation, and abnormal gait (Ref).
Mechanism: Unclear to what extent mood switches represent an uncovering of unrecognized bipolar disorder or a more direct pharmacologic effect independent of diagnosis (Ref). Mirtazapine induced-mania has been attributed to central norepinephrine hyperactivity through its unique mechanism of action of blocking central alpha-2 adrenergic autoreceptors and heteroreceptors, resulting in increased serotonin and norepinephrine neurotransmitter release while blocking postsynaptic 5-HT2 and 5-HT3 receptors (Ref).
Onset: Varied; among the limited case reports involving mirtazapine, the average time until onset of mania/hypomania following mirtazapine initiation or a dose increase was 15.7 days (median, 7 days) (Ref).
Risk factors:
• Higher doses (Ref)
• Underlying brain dysfunction (Ref)
• Coadministration with certain SSRIs (Ref)
• Family history of bipolar disorder (Ref)
• Depressive episode with psychotic symptoms (Ref)
• Younger age at onset of depression (Ref)
• Antidepressant resistance (Ref)
• Female sex (Ref)
Mirtazapine has been associated with several hyperkinetic movement disorders. Most case reports describe akathisia, acute dystonia, and restless leg syndrome (RLS). Mirtazapine-induced dyskinesia (including gradual onset, transient, and acute reversible) has also been reported rarely. Mirtazapine-induced akathisia is usually reported in the presence of higher mirtazapine doses (30 mg/day), whereas dystonia and dyskinesia are usually reported at lower doses (15 mg/day). Akathisia may also occur rarely at lower doses (15 mg/day) in select patients (Ref).
Mechanism:
Akathisia: Dose-related (likely). Mechanism has not been clearly defined, although limited data attributes akathisia to blockade of alpha-2 adrenoreceptors from higher therapeutic dosages (ie, 30 mg/day) of mirtazapine, while lower dosage may be beneficial in the treatment of akathisia due to serotonin (5-HT2A) receptor blockade (Ref).
Dystonia: Unknown, but has been attributed to antidopaminergic action due to 5-HT2 receptor inhibition associated with a central noradrenergic effect producing a noradrenergic-dopaminergic imbalance (Ref).
RLS: Unknown, but mirtazapine’s 5-HT1 stimulating properties and 5-HT2/5-HT3 receptor blocking properties have been suggested (Ref).
Dyskinesia: Unknown, but mediation by 5-HT2 receptor antagonism has been suggested, which has been shown to have some activity promoting motor function in states of reduced dopamine release (Ref).
Onset: Varied; among the case reports of mirtazapine hyperkinetic movement disorders, symptom onset occurred within 9 days, with some cases following a single dose (Ref); however, there is also a case report of mirtazapine-induced akathisia following 20 years of continuous treatment (Ref).
Risk factors:
Hyperkinetic movement disorders:
• History of drug-induced movement disorders/extrapyramidal symptoms (Ref)
Mirtazapine commonly causes increased serum cholesterol and, less commonly, increased serum triglycerides. Cases of severe hypertriglyceridemia and acute pancreatitis have also been reported rarely (some of the acute pancreatitis cases occurred in a setting of new-onset diabetes and/or diabetic ketoacidosis, making it difficult to determine whether hypertriglyceridemia was the cause) (Ref).
Mechanism: Unknown; in one study, increases in weight were linearly associated with changes in total cholesterol; however, the clinical significance is unclear, since increased cholesterol might be due to an improvement in depressive symptoms resulting in increased appetite, caloric intake, and weight (Ref).
Onset: Intermediate; increases in total cholesterol have been observed during the first 4 weeks of treatment (Ref).
Neutropenia, leukopenia, and agranulocytosis have been reported rarely with mirtazapine (Ref). Mirtazapine is also associated with drug-induced immune thrombocytopenia (DITP) (Ref).
Mechanism:
Leukopenia: Unclear and poorly understood; hypersensitivity/immune mediated mechanisms have been suggested (Ref).
DITP: Non-dose-related; immunologic; mechanism is attributed to drug-dependent antibodies that react with the glycoprotein IIb/IIIa complex on the platelet surface resulting in accelerated platelet destruction (Ref).
Onset: Varied; in general, drug-induced neutropenia usually manifests after 1 or 2 weeks of exposure and agranulocytosis usually appears 3 to 4 weeks following initiation of therapy; however, the onset may be delayed (Ref). Drug-induced thrombocytopenia generally occurs 5 to 10 days after initial drug exposure (Ref).
Mirtazapine may cause orthostatic hypotension (eg, dizziness). The actual prevalence is unknown but is likely not common (Ref).
Mechanism: Orthostatic hypotension is likely caused by antagonism of alpha-1 adrenergic receptors; mirtazapine has weak peripheral alpha-1-blocking activity (Ref), although some authors have classified it as having moderate activity (Ref).
Risk factors:
• Cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities) or cerebrovascular disease
• Known predisposing conditions (hypovolemia/dehydration)
• Concurrent medications predisposing patient to orthostatic hypotension (eg, antihypertensives)
• Older adults (≥65 years of age) (Ref)
Sedation (drowsiness) is very common with initial use and may cause nonadherence, dizziness, and confusion, particularly in older adults (Ref). However, the dose relationship with mirtazapine is unique, in that lower doses (≤15 mg) are associated with significant sedation compared to less sedation with higher doses (>15 mg) (Ref). Tolerance appears to develop to the sedative effect (Ref).
Mechanism: Dose-related (inverse relationship). Somnolence is primarily attributed to potent histamine H1 antagonism at lower doses; higher doses are less sedating due to increased noradrenergic transmission which partially offsets the antihistamine activity (Ref).
Onset: Rapid; however, tolerance appears to develop quickly (within a few days) to the sedative effect (Ref).
Risk factors:
• Concomitant use of benzodiazepines or alcohol
Serotonin syndrome has been reported rarely with mirtazapine and typically occurs with coadministration of multiple serotonergic drugs, but can occur following a single serotonergic agent at high therapeutic doses or supratherapeutic doses (Ref). Only a few cases of serotonin syndrome have been reported with mirtazapine monotherapy at therapeutic doses (Ref). Of note, some clinicians have questioned whether serotonin syndrome attributed to mirtazapine is an accurate characterization or if symptoms described are due to other causes, such as extrapyramidal symptoms (Ref). The diagnosis of serotonin syndrome is made based on the Hunter Serotonin Toxicity Criteria (Ref) and may result in a spectrum of symptoms, such as anxiety, agitation, confusion, delirium, hyperreflexia, muscle rigidity, myoclonus, tachycardia, tachypnea, and tremor. Severe cases may cause hyperthermia, significant autonomic instability (ie, rapid and severe changes in blood pressure and pulse), coma, and seizures (Ref).
Mechanism: Dose-related; mirtazapine, which does not inhibit the reuptake of serotonin, is sometimes classified as a noradrenergic and specific serotonergic antidepressant (NaSSA), and acts as an antagonist of presynaptic alpha-2 adrenergic receptors and postsynaptic 5-HT2 and 5-HT3 serotonin receptors, therefore leading to an increase in norepinephrine and 5-HT1A-mediated serotonin activity. Serotonin syndrome has been attributed to the serotonergic activity from stimulation of 5-HT1A receptors (Ref); however, some clinicians have argued that the receptor pharmacology of mirtazapine is not consistent with it being able to cause serotonin toxicity, as it does not cause serotonin (5-HT) excess in the brain (Ref).
Onset: Varied; in most serotonin-syndrome cases (74%) (predominantly involving selective serotonin reuptake inhibitors, tricyclic antidepressants, and/or monoamine oxidase inhibitors [MAOIs]), onset occurred within 24 hours of treatment initiation, overdose, or change in dose (Ref). In the few cases involving mirtazapine, most occurred within 24 hours or several days following initiation or a dose increase (Ref).
Risk factors:
• Concomitant use of drugs that increase serotonin synthesis, block serotonin reuptake and/or impair serotonin metabolism (eg, MAOIs). Of note, concomitant use of some serotonergic agents, such as MAOIs, are contraindicated.
Antidepressants, primarily the selective serotonin reuptake inhibitors, are commonly associated with sexual disorders in patients of any sex. Mirtazapine, however, is generally associated with having less risk for sexual adverse reactions and may also have some beneficial effects on sexual functioning in depressed patients (Ref). One meta-analysis also found no significant difference in treatment-emergent sexual dysfunction with mirtazapine compared to placebo (Ref).
Mechanism: The mechanism attributed to mirtazapine’s role (if any) in sexual dysfunction is unknown, and because a large portion of sexual dysfunction is thought to be mediated via stimulation of the postsynaptic 5-HT2A receptor, the blockade of this receptor by mirtazapine should lead to a reduced incidence of these side effects (Ref).
Risk factors:
• Depression (sexual dysfunction is commonly associated with depression; antidepressant-induced sexual dysfunction may be difficult to differentiate in treated patients) (Ref)
Antidepressants are associated with an increased risk of suicidal ideation and suicidal tendencies in pediatric and young adult patients (18 to 24 years of age) in short-term studies. In adults >24 years of age, short-term studies did not show an increased risk of suicidal thinking and behavior and in older adults ≥65 years of age, a decreased risk was observed. Although data have yielded inconsistent results regarding the association of antidepressants and risk of suicide, particularly among adults, collective evidence shows a trend of an elevated risk of suicidality in younger age groups (Ref). Of note, the risk of a suicide attempt is inherent in major depression and may persist until remission occurs.
Mechanism: Not established; one of several postulated mechanisms is antidepressants may energize suicidal patients to act on impulses; another suggests that antidepressants may produce a worsening of depressive symptoms leading to the emergence of suicidal thoughts and actions (Ref).
Onset: Varied; increased risk observed in short-term studies (ie, <4 months) in pediatric and young adults; it is unknown whether this risk extends to long-term use (ie, >4 months).
Risk factors:
• Children and adolescents (Ref)
• Depression (risk of suicide is associated with major depression and may persist until remission occurs)
Mirtazapine commonly causes significant weight gain (increase of ≥7% of body weight) following short and long-term use (Ref). Mirtazapine also commonly causes increased appetite (Ref).
Mechanism: Antidepressants may induce weight gain by interacting with central mechanisms regulating food intake and appetite, with differences in weight gain between agents attributed to actions on serotonergic, dopaminergic, noradrenergic, histaminergic, and cholinergic systems. Mirtazapine's weight gain has been attributed to its alpha-2 adrenoreceptor antagonism, its high affinity for antagonizing histamine (H1) receptors, and its effects on 5-HT2c receptors, as well as its low affinity for dopaminergic D1 and D2 receptors. In addition, some of the weight gain may also reflect improvement in mood (Ref).
Onset: Varied; significant increases in weight have been observed after the first week of treatment (Ref). In one meta-analysis, mirtazapine was associated with significant weight gain during acute treatment (4 to 12 weeks), and maintained significant associations with weight gain over longer periods of use (≥8 months) (Ref).
Risk factors:
• Psychiatric disorders (regardless of medication) are associated with a higher risk for obesity compared to the general population (Ref)
Withdrawal syndrome following mirtazapine discontinuation has been reported, primarily following abrupt discontinuation, although it has also occurred following gradual tapering. Reported symptoms include dizziness, nausea, vomiting, paresthesia, hypotension, insomnia, reduced need of sleep, anxiety, panic attacks, restlessness, irritability, elated mood, pressure of speech, increased energy, and nightmares (Ref). There is also a single case report of mirtazapine-withdrawal associated pruritus following abrupt discontinuation (Ref). In addition, there are several case reports describing withdrawal-induced mania or hypomania following both abrupt and gradual mirtazapine discontinuation. Some of the reports occurred in patients with bipolar disorder and some reports did not mention a preexisting diagnosis of bipolar disorder (Ref).
Mechanism: Withdrawal; mechanism of withdrawal symptoms is unknown, but has been attributed, in part, to the sudden removal of the blockade of 5-HT receptors, as stimulation of 5-HT2 and 5-HT3 receptors has been associated with nausea, anxiety, and insomnia. In addition, the sudden removal of histamine (H1) blockade may contribute to dizziness (Ref).
Onset: Varied; case reports describe an onset of withdrawal symptoms between 1 to 7 days (following either abrupt or tapered discontinuation) (Ref).
Risk factors:
• Abrupt discontinuation (rather than dose taper) or tapering the antidepressant too quickly (Ref)
• Drugs with a half-life <24 hours (eg, paroxetine, venlafaxine) (Ref)
• Higher doses (Ref)
• Longer duration of treatment (eg, ≥4 weeks) (Ref)
• Prior history of antidepressant withdrawal symptoms (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Endocrine & metabolic: Increased serum cholesterol (15% (table 1)), weight gain (12%; ≥7% of body weight: 8%; literature suggests that incidence of significant weight gain may be as high as 77% after 13.5 months of use) (table 2) (Uguz 2015)
|
Drug (Mirtazapine) |
Placebo |
Number of Patients (Mirtazapine) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|
|
15% |
7% |
N/A |
N/A |
Nonfasting cholesterol increases to ≥20% above the upper limits |
|
Drug (Mirtazapine) |
Placebo |
Number of Patients (Mirtazapine) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|
|
12% |
2% |
453 |
361 |
N/A |
|
≥7% of body weight: 8% |
0% |
N/A |
N/A |
Gastrointestinal: Constipation (13%), increased appetite (17%) (table 3), xerostomia (25%)
|
Drug (Mirtazapine) |
Placebo |
Number of Patients (Mirtazapine) |
Number of Patients (Placebo) |
|---|---|---|---|
|
17% |
2% |
453 |
361 |
Nervous system: Drowsiness (54%) (table 4)
|
Drug (Mirtazapine) |
Placebo |
Number of Patients (Mirtazapine) |
Number of Patients (Placebo) |
|---|---|---|---|
|
54% |
18% |
453 |
361 |
1% to 10%:
Cardiovascular: Edema (1%), hypertension, peripheral edema (2%), vasodilation
Dermatologic: Pruritus, skin rash
Endocrine & metabolic: Increased serum triglycerides (6%) (table 5), increased thirst
|
Drug (Mirtazapine) |
Placebo |
Number of Patients (Mirtazapine) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|
|
6% |
3% |
N/A |
N/A |
Nonfasting triglyceride increases to ≥500 mg/dL |
Gastrointestinal: Abdominal pain, anorexia, vomiting
Genitourinary: Urinary frequency (2%), urinary tract infection
Hepatic: Increased serum alanine aminotransferase (≥3 times ULN: 2%)
Nervous system: Abnormal dreams (4%), abnormality in thinking (3%), amnesia, anxiety, apathy, asthenia (8%), confusion (2%) (table 6), dizziness (7%) (table 7), hypoesthesia, malaise, myasthenia, paresthesia, psychomotor agitation, tremor (2%), twitching, vertigo
|
Drug (Mirtazapine) |
Placebo |
Number of Patients (Mirtazapine) |
Number of Patients (Placebo) |
|---|---|---|---|
|
2% |
0% |
453 |
361 |
|
Drug (Mirtazapine) |
Placebo |
Number of Patients (Mirtazapine) |
Number of Patients (Placebo) |
|---|---|---|---|
|
7% |
3% |
453 |
361 |
Neuromuscular & skeletal: Arthralgia, back pain (2%), hyperkinetic muscle activity, hypokinesia, myalgia (2%)
Respiratory: Dyspnea (1%), flu-like symptoms (5%)
<1%:
Cardiovascular: Acute myocardial infarction, angina pectoris, atrial arrhythmia, bigeminy, bradycardia, cardiomegaly, chest pain, hypotension, left ventricular failure, phlebitis, pulmonary embolism, syncope, ventricular premature contractions
Dermatologic: Alopecia, cellulitis, exfoliative dermatitis, skin photosensitivity, Stevens-Johnson syndrome, urticaria, xeroderma
Endocrine & metabolic: Amenorrhea, dehydration, diabetes mellitus, goiter, heavy menstrual bleeding, hyponatremia, hypothyroidism, increased acid phosphatase, increased libido, weight loss
Gastrointestinal: Ageusia, cholecystitis, colitis, enlargement of abdomen, enlargement of salivary glands, eructation, gastritis, gastroenteritis, gingival hemorrhage, glossitis, intestinal obstruction, nausea, oral candidiasis, pancreatitis, sialorrhea, stomatitis, tongue discoloration
Genitourinary: Breast engorgement, breast hypertrophy, cystitis, dysmenorrhea, dysuria, ejaculatory disorder, hematuria, impotence, leukorrhea, mastalgia, urethritis, urinary incontinence, urinary retention, urinary urgency, uterine hemorrhage, vaginitis
Hematologic & oncologic: Agranulocytosis, anemia, leukopenia, pancytopenia, petechia, severe neutropenia, thrombocytopenia
Hepatic: Hepatic cirrhosis, increased serum aspartate aminotransferase
Hypersensitivity: Facial edema, tongue edema
Nervous system: Akathisia, altered sense of smell, aphasia, ataxia, cerebral ischemia, chills, delirium, delusion, dementia, depersonalization, drug dependence, dysarthria, emotional lability, euphoria, extrapyramidal reaction, hallucination, hostility, hyperacusis, hyperreflexia, hypomania, hypotonia, mania, migraine, myoclonus, neurosis, paranoid ideation, seizure, serotonin syndrome, stupor, tonic-clonic seizure, vascular headache, withdrawal syndrome
Neuromuscular & skeletal: Arthritis, bone fracture (osteoporotic), dyskinesia, dystonia (including Pisa syndrome) (Yamada 2018), gout, myositis, neck pain, neck stiffness, ostealgia, rupture of tendon, tenosynovitis
Ophthalmic: Abnormal lacrimation, accommodation disturbance, angle-closure glaucoma, blepharitis, conjunctivitis, diplopia, eye pain, nystagmus disorder
Otic: Deafness, otalgia
Renal: Nephrolithiasis, polyuria
Respiratory: Epistaxis
Miscellaneous: Abnormal healing, fever, ulcer
Frequency not defined: Cardiovascular: Orthostatic hypotension
Postmarketing:
Cardiovascular: Increased serum creatine kinase, prolonged QT interval on ECG (Matsuda 2020), torsades de pointes, ventricular tachycardia
Dermatologic: Bullous dermatitis, erythema multiforme, excoriation of skin (Keshtkarjahromi 2021), hyperpigmentation (Sukhdeo 2018), toxic epidermal necrolysis
Endocrine & metabolic: Hyperglycemia (Duncan 2015), hyperprolactinemia, hypertriglyceridemia (Chen 2003, Duncan 2015)
Genitourinary: Priapism, sexual disorder (Lee 2010)
Hematologic & oncologic: Immune thrombocytopenia (Stuhec 2014)
Hepatic: Hepatotoxicity (Hui 2002), liver steatosis (Thomas 2017)
Hypersensitivity: Drug reaction with eosinophilia and systemic symptoms
Infection: Neutropenic sepsis (Maidwell-Smith 2023)
Nervous system: Complex sleep-related disorder (Shinith 2018), nightmares (Menon 2017), restless leg syndrome (precipitation or exacerbation) (Kolla 2018, Kim 2008), somnambulism (Yeh 2009), suicidal ideation, suicidal tendencies
Neuromuscular & skeletal: Rhabdomyolysis (Khandat 2004)
Hypersensitivity (eg, severe skin reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme, and toxic epidermal necrolysis) to mirtazapine or any component of the formulation; use of monoamine oxidase inhibitors (MAOIs), including IV methylene blue (concurrently or within 14 days of stopping an MAOI).
Note: Although mirtazapine is contraindicated per the manufacturer labeling when used in combination with linezolid, new evidence suggests that the combination is unlikely to cause serotonin syndrome (0.06% to 3% risk), and therefore these agents can be administered concomitantly when necessary. Monitor patients on this combination; average duration of serotonin toxicity is ~4 days; however, risks may be greater with longer durations of concurrent therapy. Educate patients on the signs and symptoms of serotonin syndrome (Bai 2022; Butterfield 2012; Karkow 2017; Kufel 2023; Narita 2007; Taylor 2006).
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. The degree of anticholinergic blockade produced by this agent is low relative to other antidepressants.
• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Leach 2017; Rabenda 2013; Rizzoli 2012).
• Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment; clearance is decreased and half-life and plasma concentrations are increased in mild to moderate impairment. Clinically significant transaminase elevations have been observed.
• Renal impairment: Use with caution in patients with renal impairment; clearance is decreased with moderate and severe renal impairment.
• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcohol use disorder, or concurrent therapy with medications that may lower seizure threshold.
Dosage form specific issues:
• Lactose: Tablets may contain lactose.
• Phenylalanine: SolTab formulation may contain phenylalanine.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Remeron: 15 mg [DSC]
Remeron: 15 mg [scored; contains corn starch]
Remeron: 30 mg [DSC]
Remeron: 30 mg [scored; contains corn starch]
Generic: 7.5 mg, 15 mg, 30 mg, 45 mg
Tablet Disintegrating, Oral:
Remeron SolTab: 15 mg, 30 mg, 45 mg [contains aspartame]
Generic: 15 mg, 30 mg, 45 mg
Yes
Tablet, orally-disintegrating (Mirtazapine Oral)
15 mg (per each): $2.35 - $2.36
30 mg (per each): $2.42 - $2.43
45 mg (per each): $2.58 - $2.59
Tablet, orally-disintegrating (Remeron SolTab Oral)
15 mg (per each): $5.87
30 mg (per each): $6.05
45 mg (per each): $6.43
Tablets (Mirtazapine Oral)
7.5 mg (per each): $2.63
15 mg (per each): $2.70 - $2.72
30 mg (per each): $2.77 - $2.80
45 mg (per each): $2.83 - $2.85
Tablets (Remeron Oral)
15 mg (per each): $7.37
30 mg (per each): $7.59
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Remeron: 30 mg [contains corn starch]
Generic: 15 mg, 30 mg, 45 mg
Tablet Disintegrating, Oral:
Remeron RD: 15 mg, 30 mg, 45 mg [contains aspartame]
Generic: 15 mg, 30 mg, 45 mg
Oral: Administer without regard to meals.
Orally disintegrating tablet: Do not remove tablet from blister pack until ready to administer; peel back foil to expose tablet; use dry hands to remove tablet and place immediately on tongue. Tablet dissolves rapidly in saliva; water is not needed. Do not chew, crush, or split tablet.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Remeron, Remeron SolTab: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020415s038,021208s028lbl.pdf#page=23
Major depressive disorder (unipolar): Treatment of unipolar major depressive disorder (MDD) in adults.
Headache, chronic tension-type, prophylaxis; Panic disorder
Remeron may be confused with Premarin, ramelteon, Rozerem, Zemuron
Beers Criteria: Mirtazapine is identified in the Beers Criteria as a potentially inappropriate medication to be used with caution in patients 65 years and older due to the potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults (Beers Criteria [AGS 2023]).
Avanza [Australia] may be confused with Albenza brand name for albendazole [US]; Avandia brand name for rosiglitazone [US, Canada, and multiple international markets]
Remeron [US, Canada, and multiple international markets] may be confused with Reneuron which is a brand name for fluoxetine [Spain]
Substrate of CYP1A2 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May enhance the CNS depressant effect of Mirtazapine. Risk X: Avoid combination
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Almotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Alosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Alpha2-Agonists: Mirtazapine may diminish the antihypertensive effect of Alpha2-Agonists. Management: Consider avoiding concurrent use. If the combination cannot be avoided, monitor for decreased effects of alpha2-agonists if mirtazapine is initiated/dose increased, or increased effects if mirtazapine is discontinued/dose decreased. Risk D: Consider therapy modification
Amphetamines: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor therapy
Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Antipsychotic Agents: Serotonergic Agents (High Risk) may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
BusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
Cimetidine: May increase the serum concentration of Mirtazapine. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Cyclobenzaprine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Mirtazapine. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Mirtazapine. Risk C: Monitor therapy
Dapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid combination
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Dexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Dextromethorphan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Doxylamine: CNS Depressants may enhance the CNS depressant effect of Doxylamine. Risk C: Monitor therapy
DroPERidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Eletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Ergot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Fenfluramine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider therapy modification
Gepirone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lasmiditan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Linezolid: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid combination
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Loxapine: CNS Depressants may enhance the CNS depressant effect of Loxapine. Risk D: Consider therapy modification
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Metaxalone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Methylene Blue: Serotonergic Non-Opioid CNS Depressants may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Metoclopramide: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors (Antidepressant): Serotonergic Non-Opioid CNS Depressants may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Antidepressant). This could result in serotonin syndrome. Risk X: Avoid combination
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Nefazodone: Mirtazapine may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the serum concentration of Mirtazapine. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and for increased mirtazapine toxicities when these agents are combined. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Ondansetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapy
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pitolisant: Mirtazapine may diminish the therapeutic effect of Pitolisant. Risk X: Avoid combination
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Psilocybin: Antidepressants may diminish the therapeutic effect of Psilocybin. Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Ramosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Rasagiline: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid combination
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Safinamide: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid combination
Selective Serotonin Reuptake Inhibitors: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Selegiline: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid combination
Serotonergic Agents (High Risk, Miscellaneous): May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Serotonergic Opioids (High Risk): Serotonergic Non-Opioid CNS Depressants may enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Non-Opioid CNS Depressants may enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modification
Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Serotonin/Norepinephrine Reuptake Inhibitors: Mirtazapine may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
St John's Wort: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Syrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Tobacco (Smoked): May decrease the serum concentration of Mirtazapine. Risk C: Monitor therapy
TraZODone: May enhance the CNS depressant effect of Mirtazapine. TraZODone may enhance the serotonergic effect of Mirtazapine. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and CNS depression when these agents are combined. Risk C: Monitor therapy
Tricyclic Antidepressants: May enhance the CNS depressant effect of Serotonergic Non-Opioid CNS Depressants. Tricyclic Antidepressants may enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and CNS depression when these agents are combined. Risk C: Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Warfarin: Mirtazapine may enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification
If treatment for major depressive disorder is initiated for the first time in females planning a pregnancy, agents other than mirtazapine are preferred (use of mirtazapine is not preferred in pregnant women) (Larsen 2015).
The incidence of sexual dysfunction with mirtazapine is generally lower than with selective serotonin reuptake inhibitors (WFSBP [Bauer 2013]).
Mirtazapine crosses the placenta (Hatzidaki 2008).
A significant increase in major teratogenic effects has not been observed following exposure to mirtazapine during pregnancy; however, information is limited (CANMAT [MacQueen 2016]; Larsen 2015).
Untreated or inadequately treated psychiatric illness may lead to poor compliance with prenatal care. Therapy with antidepressants during pregnancy should be individualized (ACOG 92 2008; CANMAT [MacQueen 2016]). Psychotherapy or other nonmedication therapies may be considered for some women; however, antidepressant medication should be considered for pregnant women with moderate to severe major depressive disorder (MDD) (APA 2010). If treatment for MDD is initiated for the first time during pregnancy, mirtazapine is not recommended (CANMAT [MacQueen 2016]; Larsen 2015; WFSBP [Bauer 2013]); mirtazapine is considered a third-line agent for the treatment of mild to moderate depression during pregnancy (CANMAT [MacQueen 2016]).
Data collection to monitor pregnancy and infant outcomes following exposure to antidepressants is ongoing. Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 18 to 45 years of age or their health care providers may contact the registry by calling 844-405-6185. Enrollment should be done as early in pregnancy as possible.
Mirtazapine and its active metabolite are present in breast milk.
The highest relative infant dose (RID) of mirtazapine located in the literature is 4.4%. Authors of the study calculated the RID following maternal administration of mirtazapine 22.5 mg/day to a woman at 6 weeks' postpartum; metabolite concentrations were not evaluated. Breast milk was sampled 4 hours after the maternal dose (Klier 2007). Desmethylmirtazpine can also be detected in breast milk (Kristensen 2007).
In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000). However, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015).
Mirtazapine can be detected in the serum of breastfed infants; adverse events have generally not been observed, although possible sedation and weight gain was noted in one case report (Kristensen 2007; Smit 2015; Tonn 2009).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Infants of mothers using psychotropic medications should be monitored daily for changes in sleep, feeding patterns, and behavior (WFSBP [Bauer 2013]) as well as infant growth and neurodevelopment (ABM [Sriraman 2015]; Sachs 2013). When first initiating an antidepressant in a breastfeeding female, agents other than mirtazapine are preferred (Berle 2011; CANMAT [MacQueen 2016]).
Some products may contain phenylalanine.
CBC; renal and hepatic function; lipid profile; weight; suicidality (during the initial 1 to 2 months of therapy or during periods of dosage adjustments).
Mirtazapine is a tetracyclic antidepressant that works by its central presynaptic alpha2-adrenergic antagonist effects, which results in increased release of norepinephrine and serotonin. It is also a potent antagonist of 5-HT2 and 5-HT3 serotonin receptors and H1 histamine receptors and a moderate peripheral alpha1-adrenergic and muscarinic antagonist; it does not inhibit the reuptake of norepinephrine or serotonin.
Onset of action:
Anxiety disorders (panic disorder): Initial effects may be observed within 2 weeks of treatment, with continued improvements through 4 to 6 weeks (WFSBP [Bandelow 2023]); some experts suggest up to 12 weeks of treatment may be necessary for response (BAP [Baldwin 2014]; Katzman 2014; WFSBP [Bandelow 2023]).
Depression: Initial effects may be observed within 1 to 2 weeks of treatment, with continued improvements through 4 to 6 weeks (Papakostas 2006; Posternak 2005; Szegedi 2009).
Absorption: Rapid and complete.
Protein binding: ~85%.
Metabolism: Extensively hepatic via CYP1A2, 2D6, 3A4 and via demethylation and hydroxylation.
Bioavailability: ~50%.
Half-life elimination: ~20 to 40 hours; increased with renal or hepatic impairment.
Time to peak, serum: ~2 hours.
Excretion: Urine (75%) and feces (15%) as metabolites.
Altered kidney function: Clearance is reduced ~30% in patients with moderate (GFR 11 to 39 mL/minute/1.73 m2) and ~50% in patients with severe (GFR <10 mL/minute/1.73 m2) kidney impairment.
Hepatic function impairment: Clearance decreased by 33% and half-life and serum concentration increased by 39% and 55%, respectively, following a single dose of mirtazapine in elderly patients with mild or moderate hepatic impairment (Mauri 2014).
Older adult: Clearance is reduced 40% in elderly men and 10% in elderly women.
Sex: Women have a longer elimination half-life (37 hours) than men (26 hours).
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